rs1799921

Positions:

• chr5-63961638-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000524.4(HTR1A):​c.82A>G​(p.Ile28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 1,613,872 control chromosomes in the GnomAD database, including 130 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0093 (9 hom., cov: 33)
  • Exomes 𝑓: 0.012 (121 hom.)
• Consequence: HTR1A NM_000524.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.833

Genes affected

HTR1A (HGNC:5286): (5-hydroxytryptamine receptor 1A) This gene encodes a G protein-coupled receptor for 5-hydroxytryptamine (serotonin), and belongs to the 5-hydroxytryptamine receptor subfamily. Serotonin has been implicated in a number of physiologic processes and pathologic conditions. Inactivation of this gene in mice results in behavior consistent with an increased anxiety and stress response. Mutation in the promoter of this gene has been associated with menstrual cycle-dependent periodic fevers. [provided by RefSeq, Jun 2012]

ENSG00000248285 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005230218).
• BP6: Variant 5-63961638-T-C is Benign according to our data. Variant chr5-63961638-T-C is described in ClinVar as [Benign]. Clinvar id is 771709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0117 (17107/1461554) while in subpopulation MID AF= 0.0187 (108/5768). AF 95% confidence interval is 0.0159. There are 121 homozygotes in gnomad4_exome. There are 8438 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1417 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HTR1A	NM_000524.4	c.82A>G	p.Ile28Val	missense_variant	1/1	ENST00000323865.5	NP_000515.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HTR1A	ENST00000323865.5	c.82A>G	p.Ile28Val	missense_variant	1/1	6	NM_000524.4	ENSP00000316244.4
HTR1A	ENST00000506598.1	c.82A>G	p.Ile28Val	missense_variant	2/2	4		ENSP00000423433.1
ENSG00000248285	ENST00000502882.1	n.97-3623A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.00932 AC: 1418 AN: 152200 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.00258

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0150

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0126

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00940 AC: 2317 AN: 246554 Hom.: 18 AF XY: 0.00971 AC XY: 1298 AN XY: 133668

Gnomad AFR exome AF: 0.00207

Gnomad AMR exome AF: 0.00832

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00505

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.0117 AC: 17107 AN: 1461554 Hom.: 121 Cov.: 31 AF XY: 0.0116 AC XY: 8438 AN XY: 727052

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.00863

Gnomad4 ASJ exome AF: 0.0100

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00568

Gnomad4 FIN exome AF: 0.0116

Gnomad4 NFE exome AF: 0.0131

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00930 AC: 1417 AN: 152318 Hom.: 9 Cov.: 33 AF XY: 0.00988 AC XY: 736 AN XY: 74474

Gnomad4 AFR AF: 0.00257

Gnomad4 AMR AF: 0.0133

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0150

Gnomad4 NFE AF: 0.0126

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0120 Hom.: 19

Bravo AF: 0.00901

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0134 AC: 115

ExAC AF: 0.00884 AC: 1072

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0161

EpiControl AF: 0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	HTR1A: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	6.1
DANN	Benign	0.81
DEOGEN2	Benign	0.12	T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.57	T;T
MetaRNN	Benign	0.0052	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.049
Sift	Benign	0.59	T;T
Sift4G	Benign	0.52	T;.
Polyphen		0.0	B;.
Vest4		0.042
MVP		0.24
MPC		0.53
ClinPred		0.00030	T
GERP RS		1.2
Varity_R		0.021
gMVP		0.14

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1799921; hg19: chr5-63257465; COSMIC: COSV99072612;